CN113185503A - Natural product Pimpirinine derivative and preparation method and application thereof - Google Patents
Natural product Pimpirinine derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a Pimpirinine derivative shown as a formula III. The invention also discloses a preparation method of the Pimpirinine derivative, which takes Pimpirinine as a lead, combines the structural characteristics of the Pimpirinine, takes indole which is cheap and easy to obtain as a raw material, modifies and reforms different sites of the skeleton structure of the indole, introduces different substituents and synthesizes a series of Pimpirinine derivatives. The Pimpirinine derivative has good bactericidal activity, shows high-efficiency and/or broad-spectrum bactericidal activity, and can be applied to crop diseases caused by fungi, bacteria and viruses.
Description
Technical Field
The invention relates to an agricultural bactericide, in particular to a natural product Pimpirinine derivative, a preparation method thereof and application thereof in sterilization.
Background
In recent years, various synthetic methods of Pimprinine analogs have been reported. In the 3- (oxazole-5-yl) indole natural product, indole is used as a main structure, so the compounds are obtained by methods such as ring closing or coupling and the like by using indole or substituted indole as a raw material in the currently reported technical methods. The existing 3- (oxazole-5-yl) indole construction method mainly comprises amide ketone ring closing, Van Leusen ring closing and metal catalytic coupling, and the methods have the defects of expensive raw materials, complex operation and environmental pollution.
Pimprine, carbendazim, boscalid and osthole are all insufficient in bactericidal activity or bactericidal range.
Disclosure of Invention
The invention aims to take Pimpirinine as a precursor, take indole which is cheap and easy to obtain as a raw material, modify and transform different sites of a skeleton structure of the Pimpirinine through iodination, Kornblum oxidation, condensation, decarboxylation, cyclization and oxidation reaction, introduce different substituents, simply and efficiently construct a 2-substituted 5- (3' -indolyl) oxazole structure, synthesize a series of Pimpirinine derivatives, and achieve the purposes of improving the physicochemical properties of the Pimpirinine derivatives, improving the bactericidal activity of the Pimpirinine derivatives and expanding the bactericidal spectrum of the Pimpirinine derivatives. The invention also relates to methods of using these compounds and compositions thereof for sterilization.
In order to solve the technical problems, the invention provides a natural product Pimprinine derivative shown as a formula III:
wherein X is selected from H, F, Cl or Br; rIIs selected from C1-C5Alkyl, thioether alkyl, cyclohexane alkyl, phenyl; rIISelected from H, C1-C5Alkyl, cyano, nitroA radical, F, Cl or Br; but does not include: x is H, RIIs methyl, ethyl or isobutyl, RIIIs H.
Preferably, X is selected from H, Cl or Br; rIIs selected from C1-C4Straight or branched chain alkyl, 2-methylthioethyl; rIISelected from H, C1-C5Alkyl groups, F, Br; but does not include: x is H, RIIs methyl, ethyl or isobutyl, RIIIs H; x is Cl or Br, RIIs 2-methylthioethyl, RIIIs H; x is Cl, RIIs methyl, RIIIs Br; x is H or Br, RIIs methyl, RIIIs F.
Specifically, the Pimprinine derivative is specifically selected from the compounds listed in table 1:
TABLE 1 Pimpirinine derivatives
Note: compound I-6b is not obtained.
As preferred compounds of Pimprinine derivatives of the invention, they are selected from: x is selected from H, RISelected from ethyl, RIIIs selected from H; x is Cl or Br, RISelected from methyl, RIIIs selected from H; x is selected from Br, RISelected from isobutyl, RIIIs selected from H; x is selected from H, RISelected from methyl, RIISelected from Br or methyl; x is selected from Br, RISelected from methyl, RIISelected from methyl.
As one technical scheme of the Pimpirinine derivative, the Pimpirinine derivative is shown as a formula I:
wherein X is selected from H, F, Cl or Br; rI' selected from C1-C5Alkyl, thioether alkyl, cyclohexane alkyl, phenyl.
According to a preferred embodiment of the inventionX is selected from H, Cl or Br; rISelected from methyl, ethyl or isobutyl, 2-methylthioethyl.
As one technical scheme of the Pimpiprinine derivative, the Pimpiprinine derivative is shown as a formula II:
wherein X is selected from H, Cl or Br; rII' selected from C1-C5Alkyl, cyano, nitro, fluorine, chlorine, bromine.
According to a preferred embodiment of the invention, X is selected from H, Cl or Br; rIISelected from 5-F, 5-Br or 4-CH3。
The invention also aims to provide a preparation method of the Pimpirinine derivative shown as the formula III,
when X is selected from H, the synthetic route is as follows:
when X is selected from Cl or Br, the synthetic route is as follows:
specifically, the preparation method of the Pimpirinine derivative shown as the formula III comprises the following steps:
step (1), Friedel-Crafts reaction: carrying out Friedel-Crafts reaction on indole or substituted indole and acetyl chloride under the catalytic action of a catalyst to obtain a compound III-2;
step (2), synthesizing Pimpirinine derivatives with X selected from H: the compound III-2 is mixed with iodine,
The amino acids shown are reacted to synthesize the substitutions through two processes of Kornblum oxidation and alpha-amino acid ring closureOxazole ring to give compound III-3;
synthesis of Pimprinine derivatives with X selected from Cl or Br: the compound III-2 is mixed with iodine,
Reacting the amino acid shown in the specification, and synthesizing a substituted oxazole ring through two processes of Kornblum oxidation and alpha-amino acid ring closure to obtain a compound III-3; and carrying out halogenation reaction on the compound III-3 and NCS or NBS to obtain the Pimpirinine derivative with X selected from Cl or Br.
The reaction solvent used in the present invention may be dichloromethane, dimethylsulfoxide, tetrahydrofuran, carbon tetrachloride, etc. The specific species may be selected according to the selection principles in the art and are well known to those skilled in the art.
It will be understood by those skilled in the art that the preparation method of pimprine derivatives according to the present invention may further include a step of purifying the obtained product, and there is no particular requirement for the purification method, and various purification methods conventionally used by those skilled in the art may be employed, for example, extraction with an extractant, drying with a drying agent, and removal of impurities by column chromatography or the like may be employed.
In the step (1), various solvents which are conventionally used by a person skilled in the art of methylene chloride are used as reaction solvents; the molar ratio of the indole or the substituted indole to the acetyl chloride is 1: 1; the molar ratio of indole or substituted indole to catalyst is 1: 1.2.
The catalyst is tin tetrachloride or various reagents conventionally used by those skilled in the art.
Specifically, firstly, dissolving indole or substituted indole in dichloromethane, cooling to 0-5 ℃ in an ice water bath, dropwise adding stannic chloride under the protection of nitrogen, removing the ice water bath, stirring at room temperature, then dropwise adding acetyl chloride, and stirring at room temperature for reaction; and after the reaction is finished, washing with water, carrying out suction filtration and drying to obtain a compound III-2.
In order to avoid the formation of a large amount of by-products in the preparation of compound III-2, the anhydrous conditions should be strictly controlled.
In the step (2), dimethyl sulfoxide or various solvents which are conventionally used by a person skilled in the art are used as reaction solvents; the molar ratio of the compound III-2 to the iodine simple substance is 1:2, and the iodine simple substance has higher reaction activity, so that the effect of introducing a substituent group can be influenced by adding all the iodine simple substance at one time, multi-site iodination and low reaction yield are caused, and therefore, the iodine simple substance used under the alkaline condition is added in batches: 1.1 equivalents for the first addition and 0.9 equivalents for the second addition; the molar ratio of the compound III-2 to the amino acid is 1: 2; the reaction temperature was 110 ℃.
In the step (3), a mixed solvent of anhydrous tetrahydrofuran and carbon tetrachloride in a volume ratio of 1:1 is used as a reaction solvent, carbon tetrachloride and tetrahydrofuran are usually used as solvents for halogenation, the tetrahydrofuran has good solubility to a substrate, and the use of the mixed solvent is beneficial to improving the reaction efficiency while ensuring the reaction.
The molar ratio of the compound III-3 to NCS or NBS is 1: 1-1.5, preferably 1: 1.1. Because the oxazole ring can have more halogenated sites, in order to improve the halogenation selectivity, NCS (N-chlorosuccinimide) or NBS (N-bromosuccinimide) is added in batches (0.6 equivalent and 0.5 equivalent), 0.6 equivalent is added firstly, the reaction progress is monitored by TLC, and the rest 0.5 equivalent is added after a large number of product points are formed, so that the complete reaction of reactants can be ensured, halogen atoms only replace 4 sites of the oxazole ring, the yield of halogenated products is improved, the yield of the chlorinated products is over 60 percent, and the yield of brominated products is over 70 percent.
The Pimpirinine derivative has good bactericidal activity, can be used for preventing and treating crop diseases caused by fungi, bacteria and viruses, and shows high-efficiency and/or broad-spectrum bactericidal activity. Therefore, the invention also aims to provide the application of the Pimprinine derivative shown as the formula III in killing pathogenic bacteria of crops.
The crop pathogenic bacteria are strawberry botrytis cinerea, rice sheath blight bacteria, tomato early blight bacteria, wheat scab bacteria, cucumber colletotrichum gloeosporioides and apple scab bacteria, and are preferably strawberry botrytis cinerea, rice sheath blight bacteria, wheat scab bacteria, cucumber colletotrichum gloeosporioides and apple scab bacteria.
The concentration of the Pimpirinine derivative is 2ppm to 200 ppm.
Compared with the prior art, the invention has the following beneficial effects:
1. according to the invention, cheap and easily-obtained indole is used as a starting raw material, and an active natural product, namely the Pimprinine derivative, can be obtained through three simple reactions, namely acylation, cyclization and halogenation; and the raw materials of 3-acetyl indole and amino acid are cheap and easy to obtain, and the reaction time is short.
2. The natural product Pimpirinine and the derivative thereof have good bactericidal activity and can be applied to crop diseases caused by fungi, bacteria and viruses.
Detailed Description
The present invention will be described in detail below by way of examples. In the following examples, the various starting materials used in the examples are commercially available and all purity grades are analytical, unless otherwise specified. The room temperature was 25 ℃. The target compounds obtained are shown in table 1.
Example 1
Synthesizing 3-acetyl indole by using indole as a raw material:
a100 mL round-bottom flask was taken, 3.51g indole (30.0mmol) was weighed and dissolved in 20.0mL dichloromethane, the ice-water bath was cooled to 0-5 deg.C, and 4.2mL (36.0mmol) anhydrous tin tetrachloride was added dropwise under nitrogen protection, then the ice-water bath was removed, stirred at room temperature for 30 minutes, followed by 2.1mL (30.0mmol) acetyl chloride being added dropwise and stirred at room temperature for 2 hours. And after the reaction is finished, washing with water, filtering, and drying to obtain the 3-acetyl indole with the yield of 71%.
Mp:188.6-191.8℃.1H NMR(400MHz,Acetone)δ10.99(s,1H),8.40–8.31(m,1H),8.23(d,J＝3.0Hz,1H),7.54–7.49(m,1H),7.29–7.17(m,2H),2.49(s,3H).
2. Synthesis of Pimpirinine and derivative skeleton thereof
3-acetyl indole is used as a raw material to synthesize the Pimpirinine and the derivative thereof (compound I-3):
taking a 50mL eggplant-shaped bottle, weighing 0.64g (4.0mmol) of 3-acetyl indole, dissolving the 3-acetyl indole in 24mL dimethyl sulfoxide, adding 1.2g (8.0mmol) of iodine elementary substance, adding the iodine elementary substance in batches (1.1 equivalent and 0.9 equivalent), heating the mixture at 110 ℃ for 1 hour, monitoring the reaction progress by TLC, adding 8.0mmol of alpha-amino acid
(see Table 1), the reaction was maintained at 110 ℃ for 10-15min, and the progress of the reaction was monitored by TLC. After completion of the reaction, 70mL of water and 50mL of saturated brine were added to the reaction system, and the mixture was extracted with ethyl acetate, and the upper organic phase was dried over anhydrous sodium sulfate for 2 hours, followed by addition of silica gel and sample mixing, followed by purification treatment by silica gel column chromatography using ethyl acetate/petroleum ether ═ 1:4(V/V) as an eluent, to obtain the product (compound I-3).
Synthesis of 4-halogenated Pimprinine and its derivatives:
synthesis of target Compound I-4: a50 mL eggplant-shaped bottle was taken, and 5mL of tetrahydrofuran, 5mL of carbon tetrachloride and 0.074g (0.55mmoL) of NCS which had been subjected to weight evaporation were sequentially added to the compound I-3(0.50mmoL), and the mixture was reacted at 45 ℃ for 2 hours, and the progress of the reaction was monitored by TLC. After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, washed by water and extracted by ethyl acetate, and then washed by saturated salt water and clear water; drying with anhydrous sodium sulfate, drying for 2 hr, filtering, adding silica gel, stirring, and purifying with silica gel column chromatography using ethyl acetate/petroleum ether (1: 8) (V/V) as eluent.
Synthesis of target Compound I-5: taking a 50mL eggplant-shaped bottle, sequentially adding a compound I-3(0.50mmoL), adding 5mL of tetrahydrofuran and 5mL of carbon tetrachloride which are subjected to heavy steaming treatment, and adding NBS for multiple times to reduce the generation of byproducts: first, 0.06g (0.30mmoL) of NBS was added, the reaction was carried out at 45 ℃ for 20min, and the reaction was monitored by TLC, and if a by-product was produced, the reaction was stopped, and if no by-product was produced, 0.04g (0.25mmoL) of NBS was further added, and the reaction was continued for 5 to 10min, and the reaction was monitored by TLC. After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, washed by water and extracted by ethyl acetate, and then washed by saturated salt water and clear water; adding anhydrous sodium sulfate, drying for 2 hours, filtering, adding silica gel, stirring, and purifying by silica gel column chromatography with ethyl acetate/petroleum ether (12-15% (volume fraction of ethyl acetate in elution) as eluent.
The obtained target compound spectrum data are as follows:
compound I-1 a: 3- (2-methyloxazol-5-yl) -indole; a light yellow powder; the yield is 53%, Mp is 202.7-204.8 ℃.1HNMR(400MHz,DMSO)δ11.50(s,1H),7.82(d,J＝7.8Hz,1H),7.71(d,J＝2.6Hz,1H),7.46(d,J＝8.0Hz,1H),7.27(s,1H),7.22–7.10(m,2H),2.47(s,3H).13C NMR(101MHz,Acetone)δ158.48,147.83,136.83,124.16,122.41,122.31,120.19,119.62,119.57,111.87,105.03,12.88.IRv/cm-1:3283.22(Pyrrolyl-CH),3143.3(NH),3053.46(C＝C-H),1636.61(C＝N),1246.90(C-N),1023.35(C-O-C).HRMS(MALDI):m/z 199.0862.Calcd.for C12H10N2O:199.0866[M+H]+.
Compound I-2 a: 3- (2-ethyl-oxazol-5-yl) -indole; a light yellow powder; the yield is 42%, Mp is 157.4-158.6 ℃.1HNMR(400MHz,DMSO)δ11.53(s,1H),7.83(d,J＝7.8Hz,1H),7.73(d,J＝2.6Hz,1H),7.46(d,J＝8.1Hz,1H),7.29(s,1H),7.16(dt,J＝25.1,7.3Hz,2H),2.82(q,J＝7.6Hz,2H),1.30(t,J＝7.6Hz,3H).13C NMR(101MHz,Acetone)δ162.87,147.68,136.84,124.20,122.47,122.33,120.22,119.66,119.42,111.90,105.08,21.19,10.78.IRv/cm-1:3213.24(Pyrrolyl-CH),3163.21(NH),2956.69(C＝C-H),1631.82(C＝N),1243.67(C-N),1116.80(C-O-C).HRMS(MALDI):m/z 213.1087.Calcd.for C13H12N2O:213.1022[M+H]+.
Compound I-3 a: 3- (2-isobutyloxazol-5-yl) -indole; a yellow powder; the yield is 43 percent, and Mp is 137.9-139.6 ℃.1HNMR(400MHz,DMSO)δ11.52(s,1H),7.81(d,J＝7.8Hz,1H),7.71(d,J＝2.6Hz,1H),7.45(d,J＝8.0Hz,1H),7.28(s,1H),7.22–7.09(m,2H),2.67(d,J＝7.1Hz,2H),2.24–2.04(m,1H),0.97(d,J＝6.7Hz,6H).13C NMR(101MHz,Acetone)δ161.36,147.69,136.83,124.19,122.47,122.31,120.21,119.65,119.42,111.89,105.09,36.62,27.44,21.75.IRv/cm-1:3126.22(Pyrrolyl-CH),3051(NH),2928.40(C＝C-H),1636.17(C＝N),1262.88(C-N),1126.44(C-O-C).HRMS(MALDI):m/z 241.1331.Calcd.for C15H16N2O:241.1335[M+H]+.
Compound I-4 a: 3- (2-cyclohexyloxazol-5-yl) -indole; a light pink powder; the yield was 53%. Mp was 177.6-179.3 ℃.1HNMR(400MHz,Acetone)δ10.67(s,1H),7.90(d,J＝7.8Hz,1H),7.74(d,J＝2.4Hz,1H),7.51(d,J＝7.8Hz,1H),7.27–7.22(m,1H),7.22–7.14(m,2H),2.87(dq,J＝11.2,3.8Hz,1H),2.17–2.09(m,2H),1.91–1.79(m,2H),1.78–1.67(m,2H),1.66–1.47(m,2H),1.45–1.32(m,2H).13C NMR(101MHz,Acetone)δ165.12,147.37,136.83,124.24,122.44,122.29,120.19,119.67,119.28,111.87,105.15,37.20,30.63,25.74,25.38.IRv/cm-1:3158.93(Pyrrolyl-CH),3130.57(NH),3056.67(C＝C-H),1635.88(C＝N),1261.15(C-N),1162.25(C-O-C).HRMS(MALDI):m/z 267.1487.Calcd.for C17H18N2O:267.1491[M+H]+.
Compound I-5 a: 3- (2-phenyloxazol-5-yl) -indole; a yellow solid; the yield is 47%, Mp is 225.6-227.8 ℃.1HNMR(400MHz,Acetone)δ10.80(s,1H),8.19–8.12(m,2H),8.04–7.99(m,1H),7.95(d,J＝2.4Hz,1H),7.59–7.48(m,5H),7.24(qd,J＝7.0,3.4Hz,2H).13C NMR(101MHz,Acetone)δ158.79,148.62,136.91,129.79,128.91,127.99,125.73,124.19,123.26,122.48,121.09,120.49,119.70,112.02,104.75.IRv/cm-1:3271(Pyrrolyl-CH),3172(NH),2929.33(C＝C-H),1632.58(C＝N),1266.90(C-N),1124.88(C-O-C).HRMS(MALDI):m/z 261.1023.Calcd.for C17H12N2O:261.1022[M+H]+.
Compound I-6 a: 3- (2- (methylthio) -ethyl oxazol-5-yl) -indole; a yellow powder; the yield is 40%, Mp is 141.2-143.2 ℃.1H NMR(400MHz,DMSO)δ11.53(s,1H),7.83(d,J＝7.8Hz,1H),7.73(d,J＝2.3Hz,1H),7.44(d,J＝8.0Hz,1H),7.30(s,1H),7.15(dt,J＝14.9,7.2Hz,2H),3.09(t,J＝7.2Hz,2H),2.90(t,J＝7.2Hz,2H),2.08(s,3H).13C NMR(101MHz,Acetone)δ160.39,147.96,136.83,124.18,122.62,122.35,120.26,119.68,119.53,111.91,104.95,30.87,28.27,14.35.IRv/cm-1:3165.25(Pyrrolyl-CH),2958.17(NH),2927.87(C＝C-H),1630.28(C＝N),1264.32(C-N),1128.91(C-O-C),1074.83(C-S-C).HRMS(MALDI):m/z 259.0900.Calcd.for C14H14N2SO:259.0900[M+H]+.
Compound I-1 b: 3- (4-chloro-2-methyloxazol-5-yl) -indole; a white powder; the yield is 65 percent, Mp is 183-185.5 ℃.1HNMR(400MHz,DMSO)δ11.72(s,1H),7.91(d,J＝7.9Hz,1H),7.84(d,J＝2.6Hz,1H),7.49(d,J＝8.0Hz,1H),7.18(dt,J＝27.2,7.2Hz,2H),2.52(s,3H).13C NMR(101MHz,Acetone)δ158.20,142.62,136.30,124.62,123.73,122.58,120.72,120.37,111.88,111.83,102.9,13.15.IRv/cm-1:3164.28(Pyrrolyl-CH),3028.72(NH),2928.72(C＝C-H),1631.4(C＝N),1289(C-N),1157.6(C-O-C),735.7(C-Cl).HRMS(MALDI):m/z 233.0478.Calcd.for C12H9ClN2O:233.0476[M+H]+.
Compound I-2 b: 3- (4-chloro-2-ethyl-oxazol-5-yl) -indole; a yellow powder; the yield is 57%, Mp is 135.4-138.1 ℃.1H NMR(400MHz,Acetone)δ10.83(s,1H),8.02(d,J＝7.9Hz,1H),7.90(s,1H),7.53(d,J＝8.1Hz,1H),7.28–7.15(m,2H),2.89(q,J＝7.6Hz,2H),1.39(t,J＝5.7Hz,3H).13C NMR(101MHz,Acetone)δ162.36,142.49,136.17,124.61,123.58,122.60,120.72,120.42,120.39,111.86,102.92,21.40,10.40.IRv/cm-1:3248.54(Pyrrolyl-CH),3126.04(NH),3075.43(C＝C-H),1627.56(C＝N),1250(C-N),1132.9(C-O-C),747.8(C-Cl).HRMS(MALDI):m/z 247.0634.Calcd.for C13H11ClN2O:247.0633[M+H]+.
Compound I-3 b: 3- (4-chloro-2-isobutyloxazol-5-yl) -indole; a light yellow powder; the yield is 80%, Mp is 106-107.7 ℃.1H NMR(400MHz,Acetone)δ10.82(s,1H),8.02(d,J＝7.9Hz,1H),8.02(d,J＝7.9Hz,1H),7.91(s,1H),7.21(dt,J＝23.9,7.2Hz,2H),2.75(d,J＝7.1Hz,2H),2.30–2.16(m,1H),1.05(d,J＝6.6Hz,6H).13C NMR(101MHz,Acetone)δ160.84,142.55,136.32,124.64,123.75,122.61,120.67,120.45,120.32,111.92,102.96,36.69,27.36,21.68.IRv/cm-1:3224.34(Pyrrolyl-CH),3176.26(NH),2956.48(C＝C-H),1630(C＝N),1245.3(C-N),1130.5(C-O-C),737.3(C-Cl).HRMS(MALDI):m/z 275.0945.Calcd.for C15H15ClN2O:275.0946[M+H]+.
Compound I-4 b: 3- (4-chloro-2-cyclohexyloxazol-5-yl) -indole; a yellow powder; the yield is 62%, Mp is 189.8-192.1 ℃.1H NMR(400MHz,Acetone)δ10.82(s,1H),8.03(d,J＝7.9Hz,1H),7.91(d,J＝2.8Hz,1H),7.54(d,J＝8.0Hz,1H),7.31–7.15(m,2H),2.94(tt,J＝11.1,3.7Hz,1H),2.17(dd,J＝13.0,3.0Hz,2H),2.06(dt,J＝4.4,2.2Hz,2H),1.90–1.81(m,2H),1.74–1.66(m,2H),1.54–1.42(m,2H).13C NMR(101MHz,Acetone)δ164.41,142.20,136.31,124.64,123.68,122.59,120.45,120.36,111.90,103.04,99.99,37.26,30.26,25.60,25.24.IRv/cm-1:3305(Pyrrolyl-CH),3165(NH),3034(C＝C-H),1626.9(C＝N),1243(C-N),1127(C-O-C),747.8(C-Cl).HRMS(MALDI):m/z301.1104.Calcd.for C17H17ClN2O:301.1102[M+H]+.
Compound I-5 b: 3- (4-chloro-2-phenyloxazol-5-yl) -indole; a light yellow powder; the yield is 57%, Mp is 191.9-194 ℃.1H NMR(400MHz,Acetone)δ10.94(s,1H),8.15(d,J＝7.5Hz,2H),8.05(s,1H),7.68–7.43(m,5H),7.33–7.23(m,2H).13C NMR(101MHz,Acetone)δ157.52,143.47,136.23,130.48,129.10,126.97,125.87,125.71,124.29,122.81,122.39,120.80,120.44,112.00,102.78.IRv/cm-1:3276.5(Pyrrolyl-CH),3048(NH),2918(C＝C-H),1627.8(C＝N),1246.3(C-N),1128(C-O-C),736.7(C-Cl).HRMS(MALDI):m/z 295.0640.Calcd.for C17H11ClN2O:295.0633[M+H]+.
Compound I-1 c: 3- (4-bromo-2-methyloxazol-5-yl) -indole; a yellow powder; the yield is 76%, Mp is 202.7-204.8 ℃.1H NMR(400MHz,DMSO)δ11.71(s,1H),7.91(t,J＝5.7Hz,2H),7.50(d,J＝8.0Hz,1H),7.22(t,J＝7.5Hz,1H),7.15(t,J＝7.4Hz,1H),2.54(s,3H).13C NMR(101MHz,Acetone)δ158.49,147.83,136.82,124.14,122.42,122.32,120.19,119.63,119.55,111.89,105.01,12.90.IRv/cm-1:3180(Pyrrolyl-CH),3038(NH),2927(C＝C-H),1627(C＝N),1284(C-N),1152.3(C-O-C),751.1(C-Br).HRMS(MALDI):m/z 276.9968.Calcd.for C12H9BrN2O:276.9971[M+H]+.
Compound I-2 c: 3- (4-bromo-2-ethyl-oxazol-5-yl) -indole; a yellow powder; the yield is 60%, Mp is 137.7-139.4 ℃.1HNMR(400MHz,Acetone)δ10.82(s,1H),8.03(d,J＝7.9Hz,1H),8.00(d,J＝2.8Hz,1H),7.53(d,J＝8.0Hz,1H),7.27–7.15(m,2H),2.94–2.87(q,2H),1.38(t,J＝7.6Hz,3H).13C NMR(101MHz,Acetone)δ163.29,144.96,136.32,124.81,124.03,122.91,122.61,120.47,111.94,107.40,103.12,21.38,10.48.IRv/cm-1:3266(Pyrrolyl-CH),3117(NH),2976(C＝C-H),1626(C＝N),1216.3(C-N),1123.4(C-O-C),749(C-Br).HRMS(MALDI):m/z 291.0132.Calcd.for C13H11BrN2O:291.0128[M+H]+.
Compound I-3 c: 3- (4-bromo-2-isobutyloxazol-5-yl) -indole; a yellow powder; the yield is 74 percent, and Mp is 105.2-106.6 ℃.1H NMR(400MHz,Acetone)δ10.84(s,1H),8.03(d,J＝7.9Hz,1H),7.91(s,1H),7.54(d,J＝8.1Hz,1H),7.27–7.15(m,2H),2.76(d,J＝7.1Hz,2H),2.30–2.17(m,1H),1.06(d,J＝4.3Hz,6H).13C NMR(101MHz,Acetone)δ160.84,142.55,136.31,124.62,123.75,123.59,122.62,120.46,120.33,111.93,102.95,36.69,27.37,21.69.IRv/cm-1:3168(Pyrrolyl-CH),3058(NH),2925(C＝C-H),1610(C＝N),1272(C-N),11567(C-O-C),739(C-Br).HRMS(MALDI):m/z319.0448.Calcd.for C15H15BrN2O:319.0441[M+H]+.
Compound I-4 c: 3- (4-bromo-2-cyclohexyloxazol-5-yl) -indole; a yellow powder; the yield is 76%, Mp is 173.8-176.6 ℃.1H NMR(400MHz,Acetone)δ10.80(s,1H),8.03(d,J＝7.9Hz,1H),8.00(s,1H),7.53(d,J＝8.0Hz,1H),7.21(dt,J＝14.8,7.2Hz,2H),3.03–2.89(m,1H),2.16(d,J＝11.2Hz,2H),1.92–1.79(m,2H),1.70(dd,J＝18.7,9.8Hz,2H),1.66–1.49(m,2H),1.36(m,J＝27.2,14.4,6.3Hz,2H).13C NMR(101MHz,Acetone)δ165.32,144.64,136.16,124.78,123.94,123.78,122.58,120.46,111.85,107.35,103.15,37.23,30.29,25.60,25.25.IRv/cm-1:3305(Pyrrolyl-CH),3120(NH),2928(C＝C-H),1624(C＝N),1242(C-N),1117(C-O-C),756.1(C-Br).HRMS(MALDI):m/z345.0602.Calcd.for C17H17BrN2O:345.0597[M+H]+.
Compound I-5 c: 3- (4-bromo-2-phenyloxazol-5-yl) -indole; a yellow powder; the yield is 70 percent, and Mp is 167-169.9 ℃.1HNMR(400MHz,Acetone)δ8.22(dd,J＝6.1,2.5Hz,1H),8.16(d,J＝1.6Hz,1H),8.15(d,J＝3.0Hz,2H),7.83–7.35(m,5H),7.28–7.26(m,1H).13C NMR(101MHz,Acetone)δ158.57,145.86,136.22,130.49,129.11,126.92,125.73,124.67,124.53,122.81,120.83,120.50,112.02,109.12,102.94.IRv/cm-1:3340(Pyrrolyl-CH),3053.6(NH),2927(C＝C-H),1625.6(C＝N),1256.8(C-N),1123.1(C-O-C),755.4(C-Br).HRMS(MALDI):m/z 339.0139.Calcd.for C17H11BrN2O:339.0128[M+H]+.
Compound I-6 c: 3- (4-bromo-2- (methylthio) -ethyl oxazol-5-yl) -indole; a light yellow powder; the yield is 53 percent, and Mp is 135.8-137.7 ℃.1H NMR(400MHz,Acetone)δ10.84(s,1H),8.06(d,J＝7.9Hz,1H),8.02(s,1H),7.53(t,J＝12.6Hz,1H),7.22(dt,J＝15.0,7.2Hz,2H),3.22(t,J＝7.3Hz,2H),3.02(t,J＝7.2Hz,2H),2.18(s,3H).13C NMR(101MHz,Acetone)δ160.84,145.26,136.15,124.76,124.12,123.95,122.63,120.50,111.87,107.44,102.97,30.63,28.25,14.34.IRv/cm-1:3277.5(Pyrrolyl-CH),3141.2(NH),2917(C＝C-H),1627.6(C＝N),1247.2(C-N),1158(C-O-C),1040.4(C-S-C),757.7(C-Br).HRMS(MALDI):m/z 337.0002.Calcd.for C14H13BrN2SO:337.0005[M+H]+.
Example 2
Synthesis of substituted-3-acetyl indole:
weighing substituted indole (3) in a 100mL round-bottom flask0.0mmol，RIISelected from 5-F, 5-Cl, 5-Br and 4-Me which are all known compounds), adding 20.0mL of dichloromethane under the protection of nitrogen gas for stirring and dissolving, cooling to 0-5 ℃ in an ice water bath, dropwise adding 4.2mL (36.0mmol) of anhydrous stannic chloride, removing the ice water bath, stirring for 30min at room temperature, dropwise adding 2.1mL (30.0mmol) of acetyl chloride, monitoring the reaction progress by TLC, adding a small amount of water for quenching after the reaction is finished, extracting with ethyl acetate and a small amount of acetone, combining organic phases, washing with water and saturated common salt water respectively, and adding anhydrous sodium sulfate for drying. After drying, the product was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1: 3) (V/V) as an eluent to obtain compound II-2.
The obtained target compound spectrum data are as follows:
5-fluoro-3-acetylindole; the yield was 53%.1H NMR(400MHz,Acetone-d6)δ(ppm)＝11.02(s,1H),8.30(dd,J＝8.8,5.6Hz,1H),8.24(d,J＝3.0Hz,1H),7.25(dd,J＝9.6,2.4Hz,1H),7.03(ddd,J＝9.8,8.7,2.4Hz,1H),2.48(s,3H).
5-chloro-3-acetylindole; the yield was 62%.1H NMR(400MHz,Acetone-d6)δ(ppm)＝11.07(s,1H),8.32–8.25(m,2H),7.56(d,J＝1.9Hz,1H),7.23(dd,J＝8.5,1.9Hz,1H),2.48(s,3H).
5-bromo-3-acetylindole; the yield is 65%.1H NMR(400MHz,Acetone-d6)δ(ppm)＝11.14(s,1H),8.51(d,J＝2.0Hz,1H),8.28(d,J＝3.1Hz,1H),7.50(d,J＝8.6Hz,1H),7.37(dd,J＝8.6,2.0Hz,1H),2.48(s,3H).
4-methyl-3-acetylindole; the yield was 53%.1H NMR(400MHz,Acetone-d6)δ(ppm)＝10.95(s,1H),8.23(d,J＝3.2Hz,1H),7.31(d,J＝8.1Hz,1H),7.15–7.07(m,1H),7.01–6.93(m,1H),2.81(s,3H),2.51(s,3H).
Synthesis of 3-oxazole indole:
adding substituted-3-acetylindole (4.0mmol, compound II-2), iodine simple substance (5.0mmol, 1.2g) and 24mL of dimethyl sulfoxide into a 100mL round-bottom flask, adding the iodine simple substance in batches (1.1 equivalent and 0.9 equivalent), reacting at 110 ℃, monitoring the reaction progress by TLC, adding L-alanine (8.0mmol, 0.72g) and iodine simple substance (3.0mmol, 0.8g) after the reaction in the first step is completed, reacting at 110 ℃ for 10-15min, and monitoring the reaction progress by TLC. After the reaction, the combined organic phases were extracted with ethyl acetate, washed with water, saturated brine and 10% sodium thiosulfate solution, and dried over anhydrous sodium sulfate. After the drying is finished, the target compound II-3 is obtained by silica gel column chromatography purification treatment by using ethyl acetate/petroleum ether (1: 4) (V/V) as an eluent, and the characterization data of each product are as follows:
compound II-1 a: 5-fluoro-3- (2-methyloxazol-5-yl) -indole; brown solid, yield 35%, m.p.218.2-219.2 ℃.1H NMR(400MHz,Acetone-d6)δ(ppm)＝10.73(s,1H),7.87(dd,J＝8.8,5.3Hz,1H),7.73(d,J＝2.5Hz,1H),7.26(dd,J＝9.8,2.4Hz,1H),7.23(s,1H),7.00(td,J＝9.3,2.4Hz,1H),2.48(s,3H).13C NMR(101MHz,DMSO-d6)δ(ppm)＝159.6(d,J＝235.7Hz),158.9,147.4,136.8(d,J＝12.9Hz),123.9(d,J＝3.3Hz),121.0(d,J＝9.9Hz),120.9,120.0,108.9(d,J＝24.2Hz),104.6,98.5(d,J＝25.8Hz),14.0.HR-MS(ESI):m/z calcd for C12H9FN2O([M+H]+)217.0772,Found 217.0772.
Compound II-2 a: 5-chloro-3- (2-methyloxazol-5-yl) -indole; yellow solid, 50% yield, m.p.213.1-214.0 ℃.1H NMR(400MHz,Acetone-d6)δ(ppm)＝10.81(s,1H),7.88(d,J＝8.6Hz,1H),7.76(d,J＝2.7Hz,1H),7.57(d,J＝1.9Hz,1H),7.24(s,1H),7.18(dd,J＝8.5,1.9Hz,1H),2.48(s,3H).13C NMR(101MHz,DMSO-d6)δ(ppm)＝159.0,147.2,137.2,127.3,124.4,122.8,121.3,120.7,120.1,112.1,104.7,14.0.HR-MS(ESI):m/z calcd for C12H9ClN2O([M+H]+)233.0476,Found 233.0472.
Compound II-3 a: 5-bromo-3- (2-methyloxazol-5-yl) -indole; yellow solid, 43% yield, m.p.219.3-220.1 ℃.1H NMR(400MHz,Acetone-d6)δ(ppm)＝10.84(s,1H),8.03(d,J＝1.8Hz,1H),7.77(d,J＝2.7Hz,1H),7.48(d,J＝8.6Hz,1H),7.33(dd,J＝8.7,1.9Hz,1H),7.25(s,1H),2.48(s,3H).13C NMR(101MHz,DMSO-d6)δ(ppm)＝159.02,147.13,135.55,125.69,125.16,124.91,122.04,120.18,114.53,113.18,104.13,14.04.HR-MS(ESI):m/z calcd for C12H9BrN2O([M+H]+)276.9971,Found 276.9971.
II-4 a: 4-methyl-3- (2-methyloxazol-5-yl) -indole; yellow solid, yield 32%, m.p. 166.1-167.2 ℃.1H NMR(400MHz,Acetone-d6)δ(ppm)＝10.75(s,1H),7.53(d,J＝2.7Hz,1H),7.37(d,J＝8.2Hz,1H),7.11(t,J＝7.7Hz,1H),7.00(s,1H),6.90(d,J＝7.1Hz,1H),2.49(s,3H),2.47(s,3H).13C NMR(101MHz,Acetone-d6)δ(ppm)＝160.2,147.4,136.9,130.0,125.9,125.3,123.9,122.3,121.5,109.7,104.0,19.5,13.1.HR-MS(ESI):m/z calcd for C13H12N2O([M+H]+)213.1022,Found 213.1024.
Synthesis of 4-chloro-3-oxazolylindole:
compound II-3(1mmol), tetrahydrofuran 10mL, and carbon tetrachloride 10mL were added to a 50mL round-bottom flask and stirred at 45-50 ℃. After the substrate was dissolved, NCS (1.1mmoL, 0.15g) was added in portions, the progress of the reaction was monitored by TLC, the solvent was removed under reduced pressure after the reaction was completed, the organic phases were combined after extraction with ethyl acetate, washed with water and saturated brine, respectively, and dried by adding anhydrous sodium sulfate. After the drying is finished, the target compound II-4 is obtained by silica gel column chromatography purification treatment by using ethyl acetate/petroleum ether (1: 4) (V/V) as an eluent, and the characterization data of each product are as follows:
compound II-1 b: 5-fluoro-3- (4-chloro-2-methyloxazol-5-yl) -indole; white solid, yield 30%, m.p.193.3-194.1 ℃.1H NMR(400MHz,Acetone-d6)δ(ppm)＝10.89(s,1H),8.00(dd,J＝8.8,5.4Hz,1H),7.94–7.86(m,1H),7.28(dd,J＝9.8,2.4Hz,1H),7.01(ddd,J＝9.7,8.8,2.4Hz,1H),2.54(s,3H).13C NMR(101MHz,Acetone-d6)δ(ppm)＝160.1(d,J＝236.8Hz),158.3,142.2,136.3(d,J＝12.8Hz),124.2(d,J＝3.3Hz),121.5(d,J＝10.2Hz),121.3,121.0,108.9(d,J＝24.7Hz),103.1,97.9(d,J＝26.2Hz),13.1.HR-MS(ESI):m/z calcd for C12H8ClFN2O([M+H]+)251.0382,Found 251.0388.
Compound II-2 b: 5-chloro-3- (4-chloro-2-methyloxazol-5-yl) -indole; white solid, 35% yield, m.p. 178.6-179.7-194.1 ℃.1H NMR(400MHz,Acetone-d6)δ(ppm)＝10.95(s,1H),7.99(d,J＝8.6Hz,1H),7.92(d,J＝2.8Hz,1H),7.63–7.54(m,1H),7.23–7.15(m,1H),2.54(s,3H).13C NMR(101MHz,Acetone-d6)δ(ppm)＝158.4,142.0,136.7,128.0,124.6,124.4,123.2,121.6,120.8,111.7,103.2,13.2.HR-MS(ESI):m/z calcd for C12H8Cl2N2O([M+H]+)267.0086,Found 267.0086.
Compound II-3 b: 5-bromo-3- (4-chloro-2-methyloxazol-5-yl) -indole; white solid, 42% yield, m.p. 221.2-222.6 ℃.1H NMR(400MHz,Acetone-d6)δ(ppm)＝11.02(s,1H),8.16(d,J＝1.9Hz,1H),7.95(d,J＝2.8Hz,1H),7.52(d,J＝8.6Hz,1H),7.37(dd,J＝8.7,1.9Hz,1H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ(ppm)＝159.0,141.9,135.1,126.1,125.9,125.4,122.4,120.7,114.7,113.3,101.8,14.3.HR-MS(ESI):m/z calcd for C12H8BrClN2O([M+H]+)310.9581,Found 310.9592.
Synthesis of 4-bromo-3-oxazol indole:
adding compound II-3(1mmoL), tetrahydrofuran 10mL and carbon tetrachloride 10mL into a 50mL round-bottom flask, stirring at 45-50 ℃, adding NBS (1.1mmoL, 0.20g) in batches after a substrate is dissolved, monitoring the reaction progress by TLC, removing the solvent under reduced pressure after the reaction is finished, extracting with ethyl acetate, combining organic phases, washing with water and saturated saline respectively, and adding anhydrous sodium sulfate for drying. After the drying is finished, the target compound II-5 is obtained by silica gel column chromatography purification treatment by using ethyl acetate/petroleum ether (1: 4) eluent, and the characterization data of each product are as follows:
compound II-1 c: 5-fluoro-3- (4-bromo-2-methyloxazol-5-yl) -indole; white solid, 41% yield, m.p. 178.6-179.8 ℃.1H NMR(400MHz,Acetone-d6)δ(ppm)＝10.89(s,1H),8.04–7.98(m,2H),7.29(dd,J＝9.7,2.4Hz,1H),7.01(td,J＝9.3,2.4Hz,1H),2.55(s,3H).13C NMR(101MHz,Acetone-d6)δ(ppm)＝160.1(d,J＝236.8Hz),159.2,144.6,136.3(d,J＝12.8Hz),124.5(d,J＝3.3Hz),121.6(d,J＝10.1Hz),121.5,108.9(d,J＝24.6Hz),107.7,103.3,97.9(d,J＝26.2Hz),13.1.HR-MS(ESI):m/z calcd for C12H8BrFN2O([M+H]+)294.9877,Found 294.9880.
Compound II-2 c: 5-chloro-3- (4-bromo-2-methyloxazol-5-yl) -indole; white solid, 43% yield, m.p.178.6-179.7 ℃.1H NMR(400MHz,Acetone-d6)δ(ppm)＝10.94(s,1H),8.04–7.98(m,2H),7.59(d,J＝1.9Hz,1H),7.19(dd,J＝8.5,1.9Hz,1H),2.55(s,3H).13C NMR(101MHz,Acetone-d6)δ(ppm)＝159.4,144.5,136.5,128.0,124.9,124.7,121.7,120.8,111.7,107.8,103.3,13.1.HR-MS(ESI):m/z calcd for C12H8BrClN2O([M+H]+)310.9581,Found 310.9586.
Compound II-3 c: 5-bromo-3- (4-bromo-2-methyloxazol-5-yl) -indole; yellow solid, 56% yield, m.p.183.5-185.2 ℃.1H NMR(400MHz,Acetone-d6)δ(ppm)＝11.02(s,1H),8.16(d,J＝2.0Hz,1H),8.05(d,J＝2.7Hz,1H),7.52(d,J＝8.7Hz,1H),7.37(dd,J＝8.7,2.0Hz,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ(ppm)＝159.94,144.35,135.07,126.28,126.10,125.42,122.52,114.68,113.31,107.91,102.06,14.19.HR-MS(ESI):m/z calcd for C12H8Br2N2O([M+H]+)354.9076,Found 354.9079.
Compound II-4 c: 4-methyl-3- (4-bromo-2-methyloxazol-5-yl) -indole; white solid, yield 49%, m.p. 151.0-151.9 ℃.1H NMR(400MHz,Acetone-d6)δ(ppm)＝10.81(s,1H),7.64(d,J＝2.8Hz,1H),7.38(d,J＝8.2Hz,1H),7.11(t,J＝7.7Hz,1H),6.91(d,J＝7.1Hz,1H),2.51(s,3H),2.37(s,3H).13C NMR(101MHz,Acetone-d6)δ(ppm)＝160.5,136.6,129.7,127.3,125.6,122.5,121.6,113.5,109.8,101.3,18.9,13.3.HR-MS(ESI):m/z calcd for C13H11BrN2O([M+H]+)291.0128,Found 291.0123.
Experimental example 3
Six kinds of common agricultural plant pathogenic fungi, namely Botrytis cinerea (Botrytis cinerea), Rhizoctonia solani (Rhizoctonia solani), early blight of tomato (Alternaria solani), Gibberella zeae (Gibberella zeae), Colletotrichum (Colletotrichum lagenarium) and apple spot (Alternaria leaf spot), are taken as experimental objects, and a hypha growth rate method is adopted to carry out primary screening on the antibacterial activity of the 17 target compounds (the compound I-1a to the compound I-6a, the compound I-1b to the compound I-5b and the compound I-1c to the compound I-6c) prepared in the example 1.
1. Experimental facility and Material preparation
Experimental equipment:
a culture dish (Hefei Xin Yuan biotechnology limited), an autoclave (TOMY SX-700), an electric heating constant temperature biochemical incubator (Shanghai Jing Macro experiment equipment limited), an eppendorf liquid-transferring gun, a double-face purifying workbench (Suzhou purifying equipment limited), a puncher and the like.
Experimental materials:
preparing a potato dextrose agar medium (PDA); before the experiment, six strains to be tested are transferred to a Potato Dextrose Agar (PDA) culture medium, the strains are cultured for 3-10 days at the temperature of 25 +/-1 ℃, and a mycelium block with the diameter of 5mm is taken from the edge of the mycelium for determination.
2. Experimental methods
2.5mg of a test compound was weighed and dissolved in 0.1mL of N, N-Dimethylformamide (DMF) to prepare a 25mg/mL mother solution, which was then dissolved in PDA medium to give a final concentration of 50. mu.g/mL of the test compound. Inoculating the prepared hypha blocks on PDA plate culture medium, culturing at 25 deg.C for 2-15d, checking and recording colony diameter, and calculating the percentage of hypha growth inhibition of each agent treatment. The control of a drug-free plate and a commercial pesticide (carbendazim, boscalid and osthole) plate is set, and the treatment method and the added solvent amount are the same as those of the experimental group. Each sample was done in triplicate.
3. Results of the experiment
Table 2 preliminary screening results of antibacterial activity [ inhibition. eta. () ] of 17 target compounds in example 1
Note: the concentration of the tested compound for the bacteriostatic activity is 50 mug/mL.
Experimental example 4
The 11 target compounds (compound II-1a to compound II-4a, compound II-1b to compound II-3b, compound II-1c to compound II-4c) prepared in example 2 were preliminarily screened for bacteriostatic activity according to the method for determining bacteriostatic test in example 3. The concentration of the test sample: 50. mu.g/mL.
TABLE 3 Primary screening results [ inhibition. eta. () ] for the bacteriostatic activities of 11 target compounds in example 2
Tables 2 and 3 show the results of primary medium sterilization tests, and the inventors concluded that:
1. the Pimpirinine derivative shows certain bacteriostatic activity on common agricultural fungi, part of bacteriostatic effects reach 80%, although a compound with the bacteriostatic rate reaching 99.9% under the concentration of 50 mu g/mL is not found, the bacteriostatic activity of part of the Pimpirinine derivative on part of fungi is obviously higher than that of commercial pesticides (carbendazim, boscalid and osthol), and the bacteriostatic activity of part of the Pimpirinine derivative is close to or obviously higher than that of Pimpirinine.
2. The bactericidal effect of introducing chain alkyl at the 2-position of the oxazole ring is better than that of cycloalkyl, phenyl and thioether such as: the two compounds containing straight-chain alkyl have the bacteriostasis rate of more than 80 percent on rhizoctonia solani of rice and the bacteriostasis rate of more than 70 percent on botrytis cinerea of strawberries, wherein the bactericidal activity of the Pimprinine derivative after the oxazole ring is halogenated at the 4-position is obviously higher than that of the unhalogenated Pimprinine derivative, and the bactericidal activity of a brominated product is slightly higher than that of a chlorinated product.
3. The inhibition rate of 17 Pimpirinine derivatives prepared in example 1 on cucumber colletotrichum is higher than that of osthole. The compounds I-2a, I-1b, I-2b, I-1c, I-2c and I-3c have high inhibitory activity on various fungi.
4. The preliminarily obtained structure-activity relationship is as follows: the indole phenyl ring is most preferably substituted with bromine at the 5-position, followed by methyl at the 4-position, then fluorine at the 5-position, and most preferably chlorine at the 5-position. Namely: 4-CH3>5-Br>5-F>5-Cl。
5. On the whole, the 4-methyl substituted indole oxazole structure II-4a and the 5-bromine substituted indole oxazole structure II-4c on the benzene ring show good broad-spectrum bactericidal activity, show good bactericidal activity on botrytis cinerea, fusarium graminearum, rhizoctonia solani, apple spot pathogen and cucumber colletotrichum, and have better inhibition rate than osthole and Pimprinine. The inhibition rate of the compounds II-3a and II-4a on apple spot pathogenic bacteria reaches more than 90 percent, and the compounds are superior to osthole and Pimprinine.
Claims (10)
1. A Pimpirinine derivative represented by formula III:
wherein X is selected from H, Cl or Br; rIIs selected from C1-C5Alkyl, thioether alkyl, cyclohexane alkyl, phenyl; rIISelected from H, C1-C5Alkyl, cyano, nitro, F, Cl, or Br; but does not include: x is H, RIIs methyl, ethyl or isobutyl, RIIIs H.
2. The Pimprinine derivative according to claim 1, wherein: x is selected from H, Cl or Br; rIIs selected from C1-C4Straight or branched chain alkyl, 2-methylthioethyl; rIISelected from H, C1-C5Alkyl groups, F, Br; but does not include: x is H, RIIs methyl, ethyl or isobutyl, RIIIs H; x is Cl or Br, RIIs 2-methylthioethyl, RIIIs H; x is Cl, RIIs methyl, RIIIs Br; x is H or Br, RIIs methyl, RIIIs F.
3. The Pimpirinine derivative shown as a formula III is characterized in that: x is selected from H, RISelected from ethyl, RIIIs selected from H; x is Cl or Br, RISelected from methyl, RIIIs selected from H; x is selected from Br, RISelected from isobutyl, RIIIs selected from H; x is selected from H, RISelected from methyl, RIISelected from Br or methyl; x is selected from Br, RISelected from methyl, RIIIs selected from methyl;
4. a method for preparing Pimpirinine derivatives according to any one of claims 1 to 3, which comprises the steps of:
when X is selected from H, the synthetic route is as follows:
when X is selected from Cl or Br, the synthetic route is as follows:
5. the method for preparing Pimprinine derivatives according to claim 4, which is characterized in that: the method comprises the following steps:
step (1), Friedel-Crafts reaction: carrying out Friedel-Crafts reaction on indole or substituted indole and acetyl chloride under the catalytic action of a catalyst to obtain a compound III-2;
step (2), synthesizing Pimpirinine derivatives with X selected from H: the compound III-2 is mixed with iodine,
Reacting the amino acid shown in the specification, and synthesizing a substituted oxazole ring through two processes of Kornblum oxidation and alpha-amino acid ring closure to obtain a compound III-3;
synthesis of Pimprinine derivatives with X selected from Cl or Br: the compound III-2 is mixed with iodine,
Reacting the amino acid shown in the specification, and synthesizing a substituted oxazole ring through two processes of Kornblum oxidation and alpha-amino acid ring closure to obtain a compound III-3; and carrying out halogenation reaction on the compound III-3 and NCS or NBS to obtain the Pimpirinine derivative with X selected from Cl or Br.
6. The method for preparing Pimprinine derivatives according to claim 5, which is characterized in that: in the step (1), dichloromethane is used as a reaction solvent; the molar ratio of the indole or the substituted indole to the acetyl chloride is 1: 1; the molar ratio of indole or substituted indole to catalyst is 1: 1.2.
7. The method for preparing Pimprinine derivatives according to claim 5, which is characterized in that: in the step (2), dimethyl sulfoxide is used as a reaction solvent; the molar ratio of the compound III-2 to the iodine is 1: 2; the molar ratio of the compound III-2 to the amino acid is 1: 2; the reaction temperature was 110 ℃.
8. The method for preparing Pimprinine derivatives according to claim 5, which is characterized in that: in the step (3), a mixed solvent of anhydrous tetrahydrofuran and carbon tetrachloride in a volume ratio of 1:1 is used as a reaction solvent; the molar ratio of the compound III-3 to NCS or NBS is 1: 1-1.5.
9. Use of the Pimprinine derivative according to any one of claims 1 to 3 for killing pathogenic bacteria of crops.
10. Use according to claim 9, characterized in that: the crop pathogenic bacteria are strawberry botrytis cinerea, rice sheath blight bacteria, tomato early blight bacteria, wheat scab bacteria, cucumber colletotrichum, and apple spot bacteria.
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| CN114644645A (en) * | 2022-03-08 | 2022-06-21 | 南京农业大学 | 3-indole-substituted phenylborozole compound and preparation method and application thereof |
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